The long-term goal of this research is to advance the understanding of cellular mechanisms that contribute to the inflammatory etiology of interstitial cystitis (IC). The immediate goal of this project is to characterize signaling pathways initiated by calcitonin gene-related peptide (CGRP) receptor activation that lead to increased production of pro-inflammatory compounds. CGRP and other neuropeptides released from sensory fibers contribute to neurogenic inflammatory pain by potently mediating vascular changes that are a hallmark of inflammation. The subsequent increase in vascular permeability leads to extravasation, emigration and activation of leukocytes at the site of injury. Activated leukocytes go on to release additional chemical mediators (e.g., prostanoids), further promoting the edema and hypersensitivity of inflammatory pain. Increasing evidence suggests that neurogenic inflammatory pain is a major component of IC pathophysiology. This study is guided by the hypothesis that CGRP is an important mediator of specific neurogenic inflammatory pain processes. Therefore, a detailed understanding of the CGRP inflammatory signaling pathway may yield insights toward new therapeutic targets for the management of IC. CGRP receptor binding sites expressed on a human monocytic cell line (THP-1) have initially been characterized. Moreover, CGRP mediated increases in cAMP, MAP kinase phosphorylation and cyclooxygenase-2(COX-2) production has been demonstrated for these THP-1 cells. However, specific relationships between these signaling pathways and CGRP receptor activation remain unclear. Aim one will investigate the hypothesis that a CGRP mediated rise in cAMP production is directly linked to an increase in COX-2 generation. Aim two will test the hypothesis that CGRP mediated induction of COX-2 leads to an increased biosynthesis of arachidonic acid metabolites known to induce swelling and hyperalgesia. Results from completion of these specific aims will further our understanding of signaling mechanisms mediated by CGRP receptor activation that participate in the pathophysiology of inflammatory pain, implicated in the etiology of IC.